This Report involves work collected under protocols 01-M-0254 (NCT00024635 ); 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); and 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983). Results this past year: 1. PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects. Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n=12) or medicated (n=16)) and 20 healthy controls (HC) underwent PET imaging using 11C-PBR28. TSPO binding was higher in MDD versus HC in the subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC). Unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers. In conclusion, this study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects. 2. Clinical Trial of the Potassium Channel Activator Diazoxide for Major Depressive Disorder Halted Due to Intolerability. Some glutamatergic modulators have demonstrated rapid and relatively sustained antidepressant properties in patients with major depressive disorder. Because the potassium channel activator diazoxide increases glutamate uptake via potassium channel activation, we hypothesized that it might exert antidepressant effects by increasing the removal of glutamate from the synaptic cleft, thereby reducing excessive glutamate transmission. This randomized, double-blind, placebo-controlled, crossover, single-site inpatient clinical study was conducted at the National Institute of Mental Health to assess the efficacy and safety of a 3-week course of diazoxide (200-400 mg daily, twice a day) versus a 3-week course of placebo in 6 participants with treatment-refractory major depressive disorder. The study was halted due to adverse effects (e.g., edema). Although the results are negative, they are an important addition to the literature in this rapidly changing field. 3. Parsing the heterogeneity of depression: An exploratory factor analysis across commonly used depression rating scales. Due to the heterogeneity of depressive symptoms-which can include depressed mood, anhedonia, negative cognitive biases, and altered activity levels-researchers often use a combination of depression rating scales to assess symptoms. This study sought to identify unidimensional constructs measured across rating scales for depression and to evaluate these constructs across clinical trials of a rapid-acting antidepressant (ketamine). Exploratory factor analysis (EFA) was conducted on baseline ratings from the Beck Depression Inventory, the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, and the Snaith-Hamilton Pleasure Rating Scale. Inpatients with major depressive disorder (n=76) or bipolar depression (n=43) were participating in clinical ketamine trials. The trajectories of the resulting unidimensional scores were evaluated in 41 subjects with bipolar depression who participated in clinical ketamine trials. The best solution, which exhibited excellent fit to the data, comprised eight factors: Depressed Mood, Tension, Negative Cognition, Impaired Sleep, Suicidal Thoughts, Reduced Appetite, Anhedonia, and Amotivation. Various response patterns were observed across the clinical trial data, both in treatment effect (ketamine versus placebo) and in degree of placebo response, suggesting that use of these unidimensional constructs may reveal patterns not observed with traditional scoring of individual instruments. The empirical identification of unidimensional constructs creates more refined scores that may elucidate the connection between specific symptoms and underlying pathophysiology. 4. Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression. Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters. Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n=126) drawn from three studies received a single subanesthetic (0.5mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the Hamilton Depression Rating Scale (HAM-D). Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change. In conclusion, from a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.